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The Role of Inflammation in Diabetic Retinopathy
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The Role of Inflammation in Diabetic Retinopathy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 12619

Special Issue Editor

Dr. Ana I. Arroba

E-Mail Website
Guest Editor
Department of Endocrinology and Metabolism, Hospital Puerta del Mar, 11009 Cádiz, Spain
Interests: inflammation; diabetic retinopathy; inflammasoma; macrophages; microglia; polarization; glial cells; Blood Retinal Barrier; immunomodulation; visual function; kinases stress; oxidative stress

Special Issue Information

Dear Colleagues,

Recent studies have revealed the principal role of immune cells and cytokines in the development and progression of diabetic retinopathy (DR). DR is considered a chronic inflammatory disease where macrophages, microglia and glial cells play a critical role in the inflammation, neovascularization and neurodegeneration of the retina, as well as the breakdown of the blood–retina barrier (BRB) in the early stage of DR. The inflammatory mediators take part in cascades that result in cellular-level responses like neurodegeneration, pericyte loss, leakage, capillary drop out, neovascularization, etc. Traditionally, immune cells are characterized into M1 and M2 phenotypes, which are considered to target the regulation of polarization and function of macrophages/microglia. The new therapies directed toward attenuating the progression of DR could be involved in modulation.

For the Special Issue “The role of inflammation in Diabetic Retinopathy”, we accept both reviews and original articles. Reviews should provide a state-of-the-art overview of retinal or eye disorders during diabetes in the context of inflammation and immunomodulation, and may also highlight new approaches to elucidate the different roles of immune cells during DR or other eye pathologies associated with DM development, progression and treatment. Original articles should address the pathophysiology of DR in experimental cell-culture environments, animal models, and in clinical practice, including new findings on biomarkers, signaling pathways, and new therapeutic strategies. Our aim for this Special Issue is to shine a light on multidisciplinary research that examines the immune cells in diabetic retinopathy from a different perspective.

Dr. Ana I. Arroba
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • diabetes
  • inflammation
  • retina
  • immunomodulation
  • microglia
  • glia
  • macrophages
  • blood–retina barrier
  • neurodegeneration
  • vascularity
  • visual function

Published Papers (6 papers)

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Research

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11 pages, 1830 KiB  
Communication
The Disorganization of Retinal Inner Layers Is Correlated to Müller Cells Impairment in Diabetic Macular Edema: An Imaging and Omics Study
by Edoardo Midena, Tommaso Torresin, Stefano Schiavon, Luca Danieli, Chiara Polo, Elisabetta Pilotto, Giulia Midena and Luisa Frizziero
Int. J. Mol. Sci. 2023, 24(11), 9607; https://doi.org/10.3390/ijms24119607 - 01 Jun 2023
Cited by 3 | Viewed by 1916
Abstract
The disorganization of retinal inner layers (DRIL) is an optical coherence tomography (OCT) biomarker strictly associated with visual outcomes in patients with diabetic macular edema (DME) whose pathophysiology is still unclear. The aim of this study was to characterize in vivo, using retinal [...] Read more.
The disorganization of retinal inner layers (DRIL) is an optical coherence tomography (OCT) biomarker strictly associated with visual outcomes in patients with diabetic macular edema (DME) whose pathophysiology is still unclear. The aim of this study was to characterize in vivo, using retinal imaging and liquid biopsy, DRIL in eyes with DME. This was an observational cross-sectional study. Patients affected by center-involved DME were enrolled. All patients underwent spectral domain optical coherence tomography (SD-OCT) and proteomic analysis of aqueous humor (AH). The presence of DRIL at OCT was analyzed by two masked retinal experts. Fifty-seven biochemical biomarkers were analyzed from AH samples. Nineteen eyes of nineteen DME patients were enrolled. DRIL was present in 10 patients (52.63%). No statistically significant difference was found between DME eyes with and without DRIL, considering the AH concentration of all the analyzed biomarkers except for glial fibrillary acidic protein (GFAP), a biomarker of Müller cells dysfunction (p = 0.02). In conclusion, DRIL, in DME eyes, seems to strictly depend on a major dysfunction of Müller cells, explaining its role not only as imaging biomarker, but also as visual function Müller cells-related parameter. Full article
(This article belongs to the Special Issue The Role of Inflammation in Diabetic Retinopathy)
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16 pages, 3037 KiB  
Article
Anti-IL17A Halts the Onset of Diabetic Retinopathy in Type I and II Diabetic Mice
by Amy Y. Zhou, Brooklyn E. Taylor, Katherine G. Barber, Chieh A. Lee, Zakary R. R. Taylor, Scott J. Howell and Patricia R. Taylor
Int. J. Mol. Sci. 2023, 24(2), 1347; https://doi.org/10.3390/ijms24021347 - 10 Jan 2023
Cited by 2 | Viewed by 1572
Abstract
There are ~463 million diabetics worldwide, and more than half have diabetic retinopathy. Yet, treatments are still lacking for non-proliferative diabetic retinopathy. We and others previously provided evidence that Interleukin-17A (IL-17A) plays a pivotal role in non-proliferative diabetic retinopathy. However, all murine studies [...] Read more.
There are ~463 million diabetics worldwide, and more than half have diabetic retinopathy. Yet, treatments are still lacking for non-proliferative diabetic retinopathy. We and others previously provided evidence that Interleukin-17A (IL-17A) plays a pivotal role in non-proliferative diabetic retinopathy. However, all murine studies used Type I diabetes models. Hence, it was the aim of this study to determine if IL-17A induces non-proliferative diabetic retinopathy in Type II diabetic mice, as identified for Type I diabetes. While examining the efficacy of anti-IL-17A as a potential therapeutic in a short-term Type I and a long-term Type II diabetes model; using different routes of administration of anti-IL-17A treatments. Retinal inflammation was significantly decreased (p < 0.05) after Type I-diabetic mice received 1 intravitreal injection, and Type II-diabetic mice received seven intraperitoneal injections of anti-IL-17A. Further, vascular tight junction protein Zonula Occludens-1 (ZO-1) was significantly decreased in both Type I and II diabetic mice, which was significantly increased when mice received anti-IL-17A injections (p < 0.05). Similarly, tight junction protein Occludin degradation was halted in Type II diabetic mice that received anti-IL-17A treatments. Finally, retinal capillary degeneration was halted 6 months after diabetes was confirmed in Type II-diabetic mice that received weekly intraperitoneal injections of anti-IL-17A. These findings provide evidence that IL-17A plays a pivotal role in non-proliferative diabetic retinopathy in Type II diabetic mice, and suggests that anti-IL-17A could be a good therapeutic candidate for non-proliferative diabetic retinopathy. Full article
(This article belongs to the Special Issue The Role of Inflammation in Diabetic Retinopathy)
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20 pages, 6466 KiB  
Article
Characterization of NLRP3 Inflammasome Activation in the Onset of Diabetic Retinopathy
by Charisse Y-J. Kuo, Jack J. Maran, Emma G. Jamieson, Ilva D. Rupenthal, Rinki Murphy and Odunayo O. Mugisho
Int. J. Mol. Sci. 2022, 23(22), 14471; https://doi.org/10.3390/ijms232214471 - 21 Nov 2022
Cited by 11 | Viewed by 2060
Abstract
The aim of this study was to characterize the role of nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome activation in the onset of diabetic retinopathy (DR) using retina and vitreous from donors without diabetes mellitus (CTL), with diabetes mellitus [...] Read more.
The aim of this study was to characterize the role of nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome activation in the onset of diabetic retinopathy (DR) using retina and vitreous from donors without diabetes mellitus (CTL), with diabetes mellitus alone (DM), and with DR. Retinal expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1), the key markers of retinal inflammation, connexin43 (Cx43) which is involved in upstream inflammasome regulation, as well as NLRP3 and cleaved caspase-1, the main markers of inflammasome activation, were evaluated using immunohistochemistry and Western blotting. Vitreous interleukin (IL)-1β and IL-18, biomarkers of the activated inflammasome, were measured using a Luminex multiplex assay. Results showed a significant increase in the number and size of Iba-1+ cells and NLRP3 expression in DM, while a significant increase in GFAP, Cx43, cleaved caspase-1 and vitreous IL-18, as well as a further increase in Iba-1 and NLRP3 was found in DR. This suggests that the inflammasome is already primed in DM before its activation in DR. Furthermore, IL-18 may act as the major effector of inflammasome activation in DR while nuclear translocation of cleaved caspase-1 may play a role in gene transcription contributing to DR onset. Full article
(This article belongs to the Special Issue The Role of Inflammation in Diabetic Retinopathy)
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14 pages, 2139 KiB  
Article
Characterization of an Immortalized Human Microglial Cell Line as a Tool for the Study of Diabetic Retinopathy
by Aurora Mazzeo, Massimo Porta and Elena Beltramo
Int. J. Mol. Sci. 2022, 23(10), 5745; https://doi.org/10.3390/ijms23105745 - 20 May 2022
Cited by 4 | Viewed by 2518
Abstract
The complexity of the retinal structure reflects on the difficulty to describe its composite cell interactions. Microglia is responsible for the immune reaction to inflammatory stimuli during diabetic retinopathy (DR), but most studies still use rodent cells. We characterized a commercially available immortalized [...] Read more.
The complexity of the retinal structure reflects on the difficulty to describe its composite cell interactions. Microglia is responsible for the immune reaction to inflammatory stimuli during diabetic retinopathy (DR), but most studies still use rodent cells. We characterized a commercially available immortalized human microglial line and tested its susceptibility to inflammation, to study the interactions between the neuro-vascular retinal portions in species-specific models. After checking the expression of microglial markers, we tried lipopolysaccharide (LPS) stimulation and several pro-inflammatory cocktails to select the best combination able to induce a significant M1 (inflammatory) response. We measured M1 induction through the expression of pro- and anti-inflammatory molecules and performed morphologic and functional assays. Marker expression confirmed the human microglial derivation of these cells. Differently from rodents, LPS did not induce a M1 profile. The best pro-inflammatory stimulus was an interleukin-1β + tumor necrosis factor-α + interferon-γ cocktail, which induced morphology changes and increased proliferation, apoptosis, migration, reactive oxygen species, and the expression of inflammatory cytokines and miRNAs. In conclusion, this microglial line proved potentially useful to investigate the cascade of events leading to DR. In perspective, co-culture models involving microvascular cells will help in the understanding of multifaceted interactions of the neurovascular unit. Full article
(This article belongs to the Special Issue The Role of Inflammation in Diabetic Retinopathy)
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Review

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17 pages, 1118 KiB  
Review
Inflammation: The Link between Neural and Vascular Impairment in the Diabetic Retina and Therapeutic Implications
by Hugo Ramos, Cristina Hernández, Rafael Simó and Olga Simó-Servat
Int. J. Mol. Sci. 2023, 24(10), 8796; https://doi.org/10.3390/ijms24108796 - 15 May 2023
Cited by 5 | Viewed by 1358
Abstract
The etiology of diabetic retinopathy (DR) is complex, multifactorial and compromises all the elements of the retinal neurovascular unit (NVU). This diabetic complication has a chronic low-grade inflammatory component involving multiple inflammatory mediators and adhesion molecules. The diabetic milieu promotes reactive gliosis, pro-inflammatory [...] Read more.
The etiology of diabetic retinopathy (DR) is complex, multifactorial and compromises all the elements of the retinal neurovascular unit (NVU). This diabetic complication has a chronic low-grade inflammatory component involving multiple inflammatory mediators and adhesion molecules. The diabetic milieu promotes reactive gliosis, pro-inflammatory cytokine production and leukocyte recruitment, which contribute to the disruption of the blood retinal barrier. The understanding and the continuous research of the mechanisms behind the strong inflammatory component of the disease allows the design of new therapeutic strategies to address this unmet medical need. In this context, the aim of this review article is to recapitulate the latest research on the role of inflammation in DR and to discuss the efficacy of currently administered anti-inflammatory treatments and those still under development. Full article
(This article belongs to the Special Issue The Role of Inflammation in Diabetic Retinopathy)
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11 pages, 273 KiB  
Review
The Role of Inflammation and Therapeutic Concepts in Diabetic Retinopathy—A Short Review
by Krzysztof Gomułka and Michał Ruta
Int. J. Mol. Sci. 2023, 24(2), 1024; https://doi.org/10.3390/ijms24021024 - 05 Jan 2023
Cited by 20 | Viewed by 2467
Abstract
Diabetic retinopathy (DR) as a microangiopathy is the most common complication in patients with diabetes mellitus (DM) and remains the leading cause of blindness among adult population. DM in its complicated pathomechanism relates to chronic hyperglycemia, hypoinsulinemia, dyslipidemia and hypertension—all these components in [...] Read more.
Diabetic retinopathy (DR) as a microangiopathy is the most common complication in patients with diabetes mellitus (DM) and remains the leading cause of blindness among adult population. DM in its complicated pathomechanism relates to chronic hyperglycemia, hypoinsulinemia, dyslipidemia and hypertension—all these components in molecular pathways maintain oxidative stress, formation of advanced glycation end-products, microvascular changes, inflammation, and retinal neurodegeneration as one of the key players in diabetes-associated retinal perturbations. In this current review, we discuss the natural history of DR with special emphasis on ongoing inflammation and the key role of vascular endothelial growth factor (VEGF). Additionally, we provide an overview of the principles of diabetic retinopathy treatments, i.e., in laser therapy, anti-VEGF and steroid options. Full article
(This article belongs to the Special Issue The Role of Inflammation in Diabetic Retinopathy)
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